Epigenetic Information – Processing Mechanism in the Brain

Lawrence Edelstein, John Smythies and Denis Noble, Editors:
Epigenetic Information - Processing Mechanism in the Brain
Theme Issue of the Philosophical Transactions of the Royal Society B 2014; 369: 1652 (198 pages)

Reviewed by John Smythies


Introduction. L. Edelstein, J. Smythies and D. Noble.


1.      DNA modifications in the mammalian brain. J. Shin, G-L. Ming and H. Song.

2.      An evolving view of epigenetic complexity in the brain. I. A. Qureshi and M.F Mehler.

3.      The methylated-DNA binding protein MBD2 enhances NGF1-A (egr-1)-mediated transciptional activation of the glucocorticoid receptor. I.C.G. Weaver, I. C. Hellstrom, S. E. Brown, S. D. Andrews, S. Dymov, J. Diorio, T-YZhong, M. Szyl, M.J. Meaney.   

4.      Long-term climbing fiber activity induces transcription of microRNAs in cerebellar Purkinje cells. N. H. Barmack, Z. Qian and V. Yakhnitsa.

5.      Systematic identification of 3’-UTR regulatory elements in activity dependent mRNA stability in hippocampal neurons. J. E. Cohen, P. R. Lee and R. D. Fields.

6.      MicroRNA-8 promotes robust motor axon targeting by coordinate regulation of cell adhesion molecules during synapse development. C. S. Lu, B Zhai, A. Mauss, M. Landgraf, S. Gygi, D.V. Vector. 

7.      The role of long non-coding RNAs in neurodevelopment, brain function and neurological disease. T. C. Roberts, K. V. Morris and M. J. A. Wood.

8.      The RNA-centered view of the synapse: Non-coding RNAs and synaptic plasticity. N. R. Smalheiser.

9.      Extracellular-vesicle type of volume transmission and tunneling-nanotube type of wiring transmission and a new dimension to brain neuro-glial networks. L. F. Agnati and K. Fuxe.

10.  The role of epigenetic-related codes in neuro-computation: dynamic hardware in the brain. L. Edelstein and J. Smythies.

11.  Multifaceted effects of oligodendoglial exosomes on neurons: impact on neuronal firing rate, signal transduction and gene regulation. D. Frölich, W. P. Kuo, C. Frühbeis, J-J. Sun, C.M. Zehadnec,  H.J. Luhann, S. Pinto, J. Toedling, J. Trotter,  E-M. Albers.  

12.  Extracellular vesicles as modulators of cell-to-cell communication in the healthy and diseased brain. D. M. Pegtel, L. Peferoen and S. Amor.

13.  Postnatal signaling with homeoprotein transcription factors. A. Prochiantz, J. Fuchs and A. A. di Nardo.

14.  MicroRNAs and synaptic plasticity—a mutual relationship. A. Aksoy-Akesl, F. Zampa and G. Schratt.

15.  Epigenetic setting and reprograming for neural cell fate determination and differentiation. T. Imamura, M. Uesaka and K. Nakashima.

16.  Analysis of the RNA content of the exosomes derived from blood serum and urine and its potential as biomarkers. M. Li, E. Zeringer, T. Barta, J. Shageman, A. Cheng,  A.V. Vlassov,

17.  .Regulation of histone H3K4 methylation in brain development and disease. E. Shen, H. Shulha,  Z. Weng, S. Akhbarian.

18.  Exosome platform, for diagnosis and monitoring of traumatic brain injury. D. D. Taylor and C. Gercel-Taylor.


EDITOR’S COMMENT: The last decade has witnessed a revolution in our understanding of how the brain works. This involves epigenetics at various levels. Until recently it was believed that neuro-computation depends of the classical mechanisms of axon spikes and local field potentials, together with a variety of G-protein-linked receptors and second messenger systems, including some involving transcription factors and new protein synthesis. The past decade has witnessed a great development in our understanding of how much of the brain's functions is controlled by a further battery of epigenetic factors. These include:

(1)   DNA and histone methylation and acetylation that switch genes on and off

(2)   a wide range of transcription factors that are exported beyond the synapse that produced them

(3)    (most importantly,) the epigenetic activity of a multitude of non-coding RNAs (including the microRNAs that block mRNAs)

(4)    carrier organelles for (these) epigenetic loads, such as exosomes.

Exosomes are small lipoprotein vesicles that bud-off from all cells and carry payloads of epigenetic molecules. These comprise varieties of RNA (including mRNAs and microRNAs), lengths of DNA, a wide variety of proteins (including transcription factors), organelles such as ion channels and receptors, lipids and others, These exosomes travel short or long distances  (via blood) and are than taken up by target cells using specific membrane bound identification factors where they discharge their cargoes. These modulate (sometimes extensively) the structure and function of the recipient cell.

We now know that these epigenetic mechanisms play a fundamental role in the development, differentiation, microanatomy, plasticity and function in all neurons. Activities such as DNA-methylation are now known to play a fundamental role in disease (see Smythies 2013 for an example in schizophrenia). In addition exosomes have an important clinical aspect since pathological cells export exosomes carrying different loads from normal cells. These can be obtained from the blood and other body fluids. The scene is now a hive of activity with specific exosome-based tests being developed for a wide variety of diseases including prion diseases, Parkinson’s disease, Alzheimer, multiple sclerosis, schizophrenia and cancer (Tislioni et al. 2014). Furthermore exosomes can be made to carry therapeutic molecules to specific locations.

This Theme Issue presents 18 selected reviews and original research from peer-acknowledged experts in their respective disciplines on some of the highlights in this nascent and rapidly developing field.

The discoveries discussed in this Theme Issue have revolutionized our view of how the brain works in both health and disease. They have radically altered our understanding of the molecular components of many diseases involving all systems and have suggested lines of diagnosis and treatment which are just beginning to be realized.




Smythies J. Schizophrenia: one coat of many colors. Front. Psychiatr. 2013. doi: 10.3389/



Tsilioni I, Panagiotidou S, Theoharides TC. Exosomes in neurologic and psychiatric

disorders. Clin Ther. 2014;36:882-8. doi: 10.1016/j.clinthera.2014.05.005. Epub 2014

Jun 7.


John Smythies

January 29, 2015